Of the 7,000 known monogenic disorders, approximately 2,000 affect the skin. While most of these are individually rare, together they represent a significant healthcare burden and afflict up to 1% of the population. For most of these disorders, there are no effective treatments that target the root cause of the problem. Nucleic acid therapies, including siRNAs, are a potential way to modify expression of disease genes in a controlled fashion, and hold real promise for improving patient lives. While traditional “small molecule” approaches to drug development have been a successful model for large pharmaceutical companies, the cost (on the order of a $1 billion) and the length of development time (10-12 years) limit their usefulness is rare inherited skin disorder. Identification of potent and selective siRNAs with limited off-target effects is now routine in many laboratories and the cost and time involved is a fraction of what is required for small molecule drug development. The missing piece in translating siRNA technology to the clinic is a robust, reproducible, economical and “patient-friendly” (i.e., little or no pain) delivery platform. Substantial effort has been invested in a variety of delivery technologies, with increasing success. However, the complexity and cost may limit clinical translation and patient compliance. For example, the first administration of siRNA to skin, and the first siRNA to target a mutant gene, was for pachyonychia congenita, a rare genodermatoses caused by mutant keratin alleles. The intradermal injection of TD101 siRNA (targets a single nt mutation [N171K] in the keratin 6a gene) resulted in improvement in the keratoderma and lesion pain, but the painfulness of the intradermal injection necessitated use of oral pain medication and a regional nerve block and prevented further enrollment in the clinical trial.